The present invention relates to a nutritional product for a person having ulcerative colitis.
The term xe2x80x9cInflammatory Bowel Diseasexe2x80x9d is a designation commonly used for two related, but distinct, chronic inflammatory conditions affecting the gastrointestinal tract, namely Crohn""s disease and ulcerative colitis. Crohn""s disease may involve any segment of the gastrointestinal tract, although characteristically the region of greatest involvement is the distal one quarter of the small intestine and the proximal colon. In ulcerative colitis the inflammation is, by definition, limited to the mucosa of the large bowel. However, the present invention is concerned only with nutritional support for a person having ulcerative colitis. The primary cause of ulcerative colitis is not currently known.
At the present time, there is no medical cure for ulcerative colitis and this chronic condition may lead to total proctocolectomy. Current medical treatment is directed toward decreasing the number, frequency and severity of acute exacerbations of inflammatory bowel disease and preventing secondary complications, but at best, the results are disappointing. Long term use of corticosteroids to downregulate the inflammatory response is a common approach to the control of intestinal inflammation. Steroids are considered to exert their antiinflammatory effects through inhibition of the release of free arachidonic acid from membrane phospholipids; Historically the long term use of immunosuppressive agents (steroids) is associated with chronic side effects such as those presented in Table 1.
Sulfasalazine is widely used to treat victims of ulcerative colitis. Sulfasalazine""s pharmacologic effects include alterations in the bacterial flora of the gut, increased colonic absorption of fluids and electrolytes, decreases in the number of B cells, interference with lymphocyte activation and natural killer activity, and inhibition of antibody secretion. The overall usefulness of sulfasalazine has been somewhat undermined by a high degree of intolerance and a frequent occurrence of adverse reactions in the patient population such as those presented in Table 1.
Antibiotics are used intermittently, particularly in the presence of severe exacerbations as are other drugs including antispasmodics and anticholinergics. It has been reported by Rosenberg et al., xe2x80x9cNutritional Aspects of Inflammatory Bowel Diseasexe2x80x9d, ANNUAL REVIEW OF NUTRITION, Vol. 5, pages 463-484, at 467 (1985) that many drug therapies used in inflammatory bowel diseases may have negative effects on nutritional status. For example, high daily doses of corticosteroids can exert an additional catabolic effect on patients who may already be under stress, and may inhibit calcium absorption by the intestine. Another example of a potentially negative drug-nutrient interaction is the interference with folate absorption by sulfasalazine via a mechanism of competitive inhibition.
Therapy for severe attacks of ulcerative colitis frequently includes special nutritional support, especially when surgical intervention is planned. Total parenteral nutrition was initially used to improve nutritional status, but later was used to enhance xe2x80x9cbowel restxe2x80x9d and induce clinical remission to avoid total proctocolectomy. However; Gonzalez-Huix et al., xe2x80x9cEnteral versus Parenteral Nutrition as Adjunct Therapy in Acute Ulcerative Colitisxe2x80x9d, THE AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol. 8, No. 2, pages 227-232 (1993) reports the results of a study which suggests that total enteral nutrition is safe and nutritionally effective in severe attacks of ulcerative colitis. This publication suggests total enteral nutrition should be regarded as the most suitable type of nutritional support in these patients. The enteral nutritional product used in this published study was Edanec HN from UNIASA, Granada, Spain which was described in the publication as set forth below in Table 2.
Gonzalez-Huix et al., compared the effects of total enteral nutrition and total parenteral nutrition in patients with acute ulcerative colitis. The final conclusions of their trials were that total parenteral nutrition does not have a primary therapeutic effect on the inflammatory process, and that xe2x80x9cbowel restxe2x80x9d is not essential for the management of acute ulcerative colitis. The main reluctance to use enteral feeding in severe ulcerative colitis has been the possibility of worsening diarrhea. Gonzalez-Huix et al. reported that only one patient out of 23 fed enterally developed diet-related diarrhea. Although a regular diet may be well-tolerated in ulcerative colitis, patients tend to reduce food intake unless they are persistently encouraged to eat. In these circumstances, tube feeding has been used to guarantee adequate energy and nutrient supply.
The UNIASA product, Edanec HN, differs considerably from the nutritional product of the present invention. For example, the new product of the present invention has a caloric density of 1.29 kcal/ml while Edanec HN has a caloric density of 0.98 kcal/ml. Our product also is lower in fat, containing approximately 21.9 g Fat/1000 kcal while Edanec HN contains approximately 36.7 g Fat/1000 kcal. The nutritional product of the present invention also contains fish oil as a source of eicosapentaenoic acid (20:5n3) and docosahexaenoic acid (22:6n3) as well as dietary fibers such as gum arabic and indigestible oligosaccharides such as fructooligosaccharides (FOS) and xylooligosaccharides (XOS). These ingredients are crucial for a product developed for a patient with ulcerative colitis.
Ulcerative colitis afflicts persons as young as 5 years old. Onset of symptoms of inflammatory bowel disease occurs before age 20 in about 40% of patients. The biggest problem in the management of ulcerative colitis in young persons is almost invariably poor dietary compliance. It has been observed by Sutton, xe2x80x9cNutritional Needs of Children with Inflammatory Bowel Diseasexe2x80x9d, NUTRITION, Vol. 18, No. 10, pages 21-25 (1992) that deficiencies of micronutrients are individually determined and relate to disease activity and site as well as dietary intake. Sutton recommends a multivitamin/mineral tablet which meets 100-150% of the Recommended Daily Allowance. This publication further reports that: (a) deficiencies of water-soluble nutrients such as folate, B12, biotin, vitamin C, niacin, riboflavin, and B6 have been reported in patients who eliminated foods such as milk, fruits and vegetables due to intolerance; (b) deficiencies of fat-soluble nutrients such as vitamins A, E and K have been reported in patients having fat malabsorption due to severe ileac disease or resection; and (c) deficiencies of minerals and trace minerals such as calcium, iron, zinc, copper and chromium, result from inadequate intake and/or reduced absorption.
Similar nutritional deficiencies in inflammatory bowel disease patients have been reported by Rosenberg et al., xe2x80x9cNutritional Aspects of Inflammatory Bowel Diseasexe2x80x9d, ANNUAL REVIEW OF NUTRITION, Vol. 5, pages 463-484 (1985). Rosenberg, et al. describe the problems of protein calorie malnutrition and deficiency of micronutrients on gastrointestinal function and structure in these terms: The patient with inflammatory bowel disease who becomes significantly malnourished may enter a vicious cycle where secondary effects of malnutrition or gastrointestinal function and structure may lead to a further increase in gastrointestinal symptoms and malabsorption, which further worsens nutrient balance. In addition, it may be assumed that malnutrition will significantly depress the patient""s ability to heal the inflammation and structural changes in the bowel. The overall therapeutic strategy must be to ensure adequate intake of nutrients while modifying dietary intake to decrease gastrointestinal symptoms.
The impact of ulcerative colitis on nutritional status can be highly significant, particularly in the pediatric age group, in whom protein and calorie requirements for growth are not likely to be met by ordinary dietary means. There is increasing evidence that a good therapeutic response can be achieved in ulcerative colitis by dietary treatment alone. Many dietary regimens have fallen short of expectations and have not been uniformly effective in promoting weight gain and wound healing or in maintaining optimal nutritional status in patients with ulcerative colitis.
The features of the present invention which are believed to be novel are set forth with particularity in the appended claims. The present invention may be understood by referring to the following detailed description, taken in accordance with the accompanying drawing FIGS. 1-5, which are all charts presenting the results of experiments relating to the present invention.
The major advantages of using a specially formulated enteral diet to induce remission of active disease include the virtual absence of side effects, possible decreased dosage of prescribed drugs and improved nutritional status of adults and children. In order to understand and evaluate the effects of polymeric diet(s), various nutrients such as n-3 fatty acids, nutrients which function as antioxidants, and short chain fatty acids (SCFAs) must be assessed as to their ability to decrease disease activity in ulcerative colitis and allow for mucosal repair.
Increasing interest has been generated in the use of enemas/irrigation solutions containing buffered, physiologic levels of SCFAs for the treatment of diversion colitis and ulcerative colitis. Diversion colitis is an inflammatory process arising in segments of the colorectum at various intervals after surgical diversion of the fecal stream. The endoscopic appearance is similar to those of active Crohn""s Disease and ulcerative colitis. Glotzer et al., xe2x80x9cProctitis and Colitis Following Diversion of the Fecal Streamxe2x80x9d, GASTROENTEROLOGY Vol. 80, pages 438-441 (1981). The cause of this condition is not known, but one mechanism has been postulated; a nutritional deficiency of the colonic epithelium, specifically due to the absence of SCFAs normally present in colonic contents, Komorowski, xe2x80x9cHistologic Spectrum of Diversion Colitisxe2x80x9d AMERICAN JOURNAL OF SURGICAL PATHOLOGY, Vol. 14, page 548 (1990), Roediger, xe2x80x9cThe Starved Colonxe2x80x94Diminished Mucosal Nutrition, Diminished Absorption, and Colitisxe2x80x9d, DISEASES OF THE COLON AND RECTUM, Vol. 33, pages 858-862 (1990). Harig et al., xe2x80x9cTreatment of Diversion Colitis with Short-Chain-Fatty Acid Irrigationxe2x80x9d, NEW ENGLAND JOURNAL OF MEDICINE, Vol. 310, pages 23-28 (1989) tested this hypothesis by assessing whether irrigation with SCFAs could ameliorate inflammation in four patients with diversion colitis. These patients were administered SCFAs twice daily for 2-3 weeks with 60 mL of an enema solution comprising a physiologic mixture of SCFAs as sodium salts. After 2-3 weeks of therapy, macroscopic and histological resolution of inflammation was evident. An impaired utilization of SCFAs has also been implicated in ulcerative colitis which suggests that diminished intracellular energy production may be important in the inflammatory process, Roediger, xe2x80x9cThe Colonic Epithelium in Ulcerative Colitis: an Energy Deficiency Disease?xe2x80x9d, THE LANCET, Vol. 2, pages 712-715 (1980). Vernia et al., xe2x80x9cFecal Lactate and Ulcerative Colitisxe2x80x9d, GASTROENTEROLOGY, Vol. 95, pages 1564-1568 (1988); and Vernia et al., xe2x80x9cOrganic Anions and the Diarrhea of Inflammatory Bowel Diseasexe2x80x9d, DIGESTIVE DISEASES AND SCIENCES, Vol. 33, pages 1353-1358 (1988) have shown that fecal water from patients with ulcerative colitis contains reduced concentrations of SCFAs as well as markedly increased lactate and low pH. In a study by Breuer et al., xe2x80x9cRectal Irrigation with Short-Chain Fatty Acids for Distal Ulcerative Colitisxe2x80x9d (preliminary report), DIGESTIVE DISEASES AND SCIENCES, Vol. 36, pages 185-187 (1991), relates an investigation of large bowel irrigation with SCFAs in patients with ulcerative colitis. It was found that 9 out of 10 patients completing the study were judged to be at least much improved and showed a significant change in mean disease activity index score and mucosal histology score. Recently Senagore et al., xe2x80x9cShort-Chain Fatty Acid Enemas: a Cost Effective Alternative in the Treatment of Nonspecific Proctosigmoiditisxe2x80x9d, DISEASES OF THE COLON AND RECTUM, Vol. 35, page 923 (1992), confirmed the results of Breuer et al. demonstrating an 80 percent response rate in patients with idiopathic proctosigmoiditis. This study indicates that administering a solution of SCFAs similar to Harig et al. for six weeks was equally efficacious to corticosteroid or 5-ASA enemas for the treatment of proctosigmoiditis at a significant cost savings. Scheppach et al., xe2x80x9cEffect of Butyrate Enemas on the Colonic Mucosa in Distal Ulcerative Colitisxe2x80x9d, GASTROENTEROLOGY, Vol. 103, pages 51-56 (1992) investigated the use of butyrate enemas alone rather than the SCFA mixture to treat ten patients with distal ulcerative colitis in a placebo-controlled, single-blind, randomized trial. The authors concluded that markedly improved disease activity index and histological parameters suggesting that the effect of a SCFA mixture on the inflamed mucosa in ulcerative colitis is largely attributable to its butyrate moiety.
It is unlikely that short chain fatty acids added directly to an enteral product would reach the large bowel. Also, the stability of these compounds in a nutritional product is questionable. However, the nutritional product of the present invention takes advantage of the positive effect of SCFAs by providing dietary fiber or indigestible oligosaccharides.
For the purpose of the patent the following terms are defined as follows:
Dietary Fiberxe2x80x94A material that contains a large carbohydrate moiety (Degree of polymerization greater than 20 and/or a molecular weight greater than 3,600) that is resistant to endogenous digestion in the human upper digestive tract.
Indigestible Oligosaccharidexe2x80x94A small carbohydrate moiety (Degree of polymerization less than 20 and/or a molecular weight less than 3,600) that is resistant to endogenous digestion in the human upper digestive tract.
Indigestable Carbohydratexe2x80x94A term used to encompass both dietary fiber and indigestible oligosaccharides.
Certain of the organisms that inhabit the large bowel can utilize dietary fiber (eg, pectin and gum arabic) and indigestible oligosaccharides (eg, fructooligosaccharides and xylooligosaccharides) as an energy source. Smith et al., xe2x80x9cIntroduction to Metabolic Activities of Intestinal Bacteriaxe2x80x9d, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol. 32, pages 149-157 (1979); Miller et al., xe2x80x9cFermentation by Saccharolytic Intestinal Bacteriaxe2x80x9d, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol. 32, pages 164-172 (1979); Cummings., xe2x80x9cFermentation in the Human Large Intestine: Evidence and Implications for Healthxe2x80x9d, THE LANCET, Vol. 1, pages 1206-1209 (1983); Titgemeyer et al., xe2x80x9cFermentability of Various Fiber Sources by Human Fecal Bacteria In Vitroxe2x80x9d, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol. 53, pages 1418-1424 (1991). The microorganisms derive energy from the carbohydrate sources through a process referred to as anaerobic fermentation. During fermentation, the microorganisms produce SCFAs (eg, acetate, propionate, butyrate) as the major end products. Salyers et al., xe2x80x9cFermentation of Mucin and Plant Polysaccharides by Strains of Bacteroides from the Human Colonxe2x80x9d, APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Vol. 33, pages 319-322 (1977); Mitsuoka et al., xe2x80x9cEffect of Fructo-oligosaccharides on Intestinal Microfloraxe2x80x9d, DIE NAHRUNG, Vol. 31, pages 427-436 (1987); Tokunaga et al., xe2x80x9cInfluence of Chronic Intake of a New Sweetener Fructooligosaccharide (Neosugar) on growth and Gastrointestinal Function of the Ratxe2x80x9d, JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY, Vol. 32, pages 111-121 (1986).
As an indirect source of SCFAs, dietary fiber and indigestible oligosaccharides (indigestable carbohydrate) can elicit certain metabolic benefits. Total parenteral nutrition (TPN) or the administration of a fiber free liquid diet leads to reduced colonic cell proliferation and atrophy. Janne et al., xe2x80x9cColonic Mucosal Atrophy Induced by a Liquid Elemental Diet in Ratsxe2x80x9d, DIGESTIVE DISEASES, Vol. 22, pages 808-812 (1977); Morin et al., xe2x80x9cSmall Intestinal and Colonic Changes Induced by a Chemically Defined Dietxe2x80x9d, DIGESTIVE DISEASE SCIENCE, Vol 25, pages 123-128 (1980); Sircar et al., xe2x80x9cEffect of Synthetic Diets on Gastrointestinal Mucosal DNA Synthesis in Ratsxe2x80x9d, AMERICAN JOURNAL OF PHYSIOLOGY, Vol. 244, pages G327-G335 (1983); Ryan et al., xe2x80x9cEffects of Various Diets on Colonic Growth in Ratsxe2x80x9d, GASTROENTEROLOGY, Vol. 77, pages 658-663 (1979); Storme et al., xe2x80x9cThe Effects of a Liquid Elemental Diet on Cell Proliferation in the Colon of ratsxe2x80x9d, CELL TISSUE RESEARCH, Vol. 216, Pages 221-225 (1981). Such atrophy could be prevented with the use of indigestible carbohydrate. Indigestible carbohydrate, through the production of SCFAs during their fermentation, can stimulate colonic epithelial cell proliferation. Goodlad et al., xe2x80x9cProliferation Effects of Fibre on the Intestinal Epitheliumxe2x80x9d, GUT, Vol. 28 pages 221-226 (1987); Kripe et al., xe2x80x9cStimulation of Intestinal Mucosal Growth with Intracolonic Infusion of Short-Chain fatty Acidsxe2x80x9d, JOURNAL OF PARENTERAL AND ENTERAL NUTRITION, Vol. 13, pages 109-116 (1989); Scheppach et al., xe2x80x9cEffect of Short-chain Fatty Acids on the Human Colonic Mucosa In Vitroxe2x80x9d, JOURNAL OF PARENTERAL AND ENTERAL NUTRITION, Vol. 16, pages 43-48 (1992); Sakata., xe2x80x9cStimulatory Effect of Short-chain Fatty Acids on Epithelial Cell Proliferation in the Rat Intestine: A Possible Explanation for Trophic Effects of Fermentable Fibre, Gut Microbes and Luminal Trophic Factorsxe2x80x9d, BRITISH JOURNAL OF NUTRITION, Vol. 58, pages 95-103 (1987); Thomas et al., xe2x80x9cEffect of enteral Feeding on Intestinal Epithelial Proliferation and fecal Bile Acid Profiles in the Ratxe2x80x9d, JOURNAL OF PARENTERAL AND ENTERAL NUTRITION, Vol. 17, pages 210-213 (1993). A recent animal study also has demonstrated the benefit of an indigestible carbohydrate in the treatment of experimental colitis. Rolandelli et al., xe2x80x9cComparison of Parenteral Nutrition and Enteral Feeding with Pectin in Experimental Colitis in the Ratxe2x80x9d, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol. 47, pages 15-21 (1988). Specifically, the degree of bowel injury in experimental colitis was decreased when rats were fed an enteral diet supplemented with pectin, which is a dietary fiber. Improvements in outcome may have been due to the SCFAs produced during the fermentation of pectin.